Substituted pyrrolo[2,3-b]pyridines, pyrazolo[3,4-d]pyrimidines and [1,2,3]triazolo[4,5-b]pyridines as potent antivirals

ABSTRACT

The present technology provides compounds according to Formula I expected to be useful in inhibiting an enterovirus, paramyxovirus, respiratory virus, flaviviridae virus, bunyaviridae virus, togaviridae virus, or rabies virus in a cell and/or treating subjects suffering from an enterovirus, paramyxovirus, respiratory virus, flaviviridae virus, bunyaviridae virus, togaviridae virus, or rabies virus.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase Application under 35 U.S.C. §371 of International Application No. PCT/US2018/052965, filed Sep. 26,2018, which claims the benefit of priority to U.S. ProvisionalApplication No. 62/564,182, filed on Sep. 27, 2017, the entiredisclosure of each of which is herein incorporated by reference for anyand all purposes.

U.S. GOVERNMENT LICENSE RIGHTS

This invention was made with Government support under AI107383, awardedby the National Institutes of Health. The Government has certain rightsin the invention.

FIELD

The present technology generally relates to pyridine-containingcompounds useful in inhibiting an enterovirus, paramyxovirus,respiratory virus, flaviviridae virus, bunyaviridae virus, togaviridaevirus, or rabies in cells and/or treating subjects suffering from anenterovirus, paramyxovirus, respiratory virus, flaviviridae virus,bunyaviridae virus, togaviridae virus, or rabies.

BACKGROUND

Throughout this disclosure, various publications, patents and publishedpatent specifications are referenced by an identifying citation. Alsowithin this disclosure are Arabic numerals referring to referencedcitations, the full bibliographic details of which are providedimmediately after the Examples section. The disclosures of thesepublications, patents and published patent specifications are herebyincorporated by reference into the present disclosure to more fullydescribe the state of the art to which this invention pertains.

The human enteroviruses (EVs) are a genus of more than 110 serologicallydistinct, small, non-enveloped RNA viruses responsible forpoliomyelitis, encephalitis, acute heart failure, fulminant sepsis innewborns, and other life-threatening infections (Cherry, J. D. et al.(2009) Enteroviruses and Parechoviruses, in Textbook of PediatricInfectious Diseases, R. D. Feigin, et al., Editors. 2009, WB SaundersCo: Philadelphia, Pa.:1984-2041). While immunization has curtailedcirculation of the polioviruses in most of the world, other EVs(coxsackieviruses, echoviruses, and numbered EVs) continue to causesubstantial morbidity and mortality.

For example, enterovirus 71 (EV71) has been the cause of numerousepidemics of central nervous system infection in Europe and theAsia-Pacific Region over the last 15 years (McMinn, P. et al. (2001)Clin Infect Dis. 32(2):236-242; McMinn, P. C. (2002) FEMS Microbiol Rev.26(1):91-107), including an outbreak earlier in 2012 in Cambodia thatcaused more than 60 deaths (Seiff, A. (2012) Lancet 380(9838):206). Arecent outbreak of coxsackievirus B1 (CVB1) myocarditis in the UnitedStates also highlighted the mutability of enteroviruses and theirepidemic potential. A new variant of CVB1 emerged in 2007 that wasdetected at nearly 50 sites in the U.S. linked to clusters of cases ofsepsis, myocarditis, and deaths among newborns (Verma, N. A. et al.(2009) Clin Infect Dis. 49(5):759-763; Wikswo, M. E. et al. (2009) ClinInfect Dis. 49(5):e44-e51). In 2011 and 2012, cases of severe Hand,Foot, and Mouth Disease associated with coxsackievirus A6 requiringhospitalization were reported in four states.

SUMMARY

In an aspect, a compound represented by Formula I is provided

or a pharmaceutically acceptable salt thereof. In Formula I, R¹ is H,alkyl, cycloalkyl, awl, or heteroaryl; R² is a substituted orunsubstituted aryl or heteroaryl; R³ is a substituted or unsubstitutedcycloalkyl, aryl, or heteroaryl; and (a) X¹ is N, Y¹ is N, and Z¹ is CH;or (b) X¹ is N, Y¹ is CH, and Z¹ is N; or (c) X¹ is CH, Y¹ is CH, and Z¹is CH.

In an aspect, a composition is provided that includes a compound ofFormula I and a pharmaceutically acceptable carrier.

In an aspect, a pharmaceutical composition for treating an enterovirus,paramyxovirus, respiratory virus, flaviviridae virus, bunyaviridaevirus, togaviridae virus, or rabies virus infection is provided wherethe composition includes an effective amount of a compound of Formula Iand a pharmaceutically acceptable excipient.

In an aspect, a method for inhibiting the replication of an enterovirus,paramyxovirus, respiratory virus, flaviviridae virus, bunyaviridaevirus, togaviridae virus, or rabies virus in a cell infected with theenterovirus, paramyxovirus, respiratory virus, flaviviridae virus,bunyaviridae virus, togaviridae virus, or rabies virus is provided. Themethod includes contacting an effective amount of a compound of FormulaI with the cell.

In an aspect, a method of inhibiting death of a cell infected with anenterovirus, paramyxovirus, respiratory virus, flaviviridae virus,bunyaviridae virus, togaviridae virus, or rabies virus, the methodcomprising contacting an effective amount of a compound of Formula Iwith the cell.

In an aspect, a method of treating a patient or animal infected with anenterovirus, paramyxovirus, respiratory virus, flaviviridae virus,bunyaviridae virus, togaviridae virus, or rabies virus is provided, themethod including administration of an effective amount of a compound ofFormula I to the patient or animal. In the method, administration of theeffective amount of the compound to the patient or animal treats thepatient or animal infected with the enterovirus, paramyxovirus,respiratory virus, flaviviridae virus, bunyaviridae virus, togaviridaevirus, or rabies virus.

DETAILED DESCRIPTION

The following terms are used throughout as defined below.

As used herein and in the appended claims, singular articles such as “a”and “an” and “the” and similar referents in the context of describingthe elements (especially in the context of the following claims) are tobe construed to cover both the singular and the plural, unless otherwiseindicated herein or clearly contradicted by context. Recitation ofranges of values herein are merely intended to serve as a shorthandmethod of referring individually to each separate value falling withinthe range, unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., “such as”) provided herein, is intended merely to betterilluminate the embodiments and does not pose a limitation on the scopeof the claims unless otherwise stated. No language in the specificationshould be construed as indicating any non-claimed element as essential.

As used herein, “about” will be understood by persons of ordinary skillin the art and will vary to some extent depending upon the context inwhich it is used. If there are uses of the term which are not clear topersons of ordinary skill in the art, given the context in which it isused, “about” will mean up to plus or minus 10% of the particular term.

Generally, reference to a certain element such as hydrogen or H is meantto include all isotopes of that element. For example, if an R group isdefined to include hydrogen or H, it also includes deuterium andtritium. Compounds comprising radioisotopes such as tritium, C¹⁴, P³²and S³⁵ are thus within the scope of the present technology. Proceduresfor inserting such labels into the compounds of the present technologywill be readily apparent to those skilled in the art based on thedisclosure herein.

In general, “substituted” refers to an organic group as defined below(e.g., an alkyl group) in which one or more bonds to a hydrogen atomcontained therein are replaced by a bond to non-hydrogen or non-carbonatoms. Substituted groups also include groups in which one or more bondsto a carbon(s) or hydrogen(s) atom are replaced by one or more bonds,including double or triple bonds, to a heteroatom. Thus, a substitutedgroup is substituted with one or more substituents, unless otherwisespecified. In some embodiments, a substituted group is substituted with1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groupsinclude: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy,aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,and heterocyclylalkoxy groups; carbonyls (oxo); carboxylates; esters;urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols;sulfides; sulfoxides; sulfones; sulfonyls; pentafluorosulfanyl (i.e.,SF₅), sulfonamides; amines; N-oxides; hydrazines; hydrazides;hydrazones; azides; amides; ureas; amidines; guanidines; enamines;imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines;nitro groups; nitriles (i.e., CN); and the like.

Substituted ring groups such as substituted cycloalkyl, aryl,heterocyclyl and heteroaryl groups also include rings and ring systemsin which a bond to a hydrogen atom is replaced with a bond to a carbonatom. Therefore, substituted cycloalkyl, aryl, heterocyclyl andheteroaryl groups may also be substituted with substituted orunsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

Alkyl groups include straight chain and branched chain alkyl groupshaving from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or,in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms.Examples of straight chain alkyl groups include groups such as methyl,ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octylgroups. Examples of branched alkyl groups include, but are not limitedto, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl,and 2,2-dimethylpropyl groups. Representative substituted alkyl groupsmay be substituted one or more times with substituents such as thoselisted above, and include without limitation haloalkyl (e.g.,trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.

Cycloalkyl groups include mono-, bi- or tricyclic alkyl groups havingfrom 3 to 12 carbon atoms in the ring(s), or, in some embodiments, 3 to10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Exemplary monocycliccycloalkyl groups include, but not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In someembodiments, the cycloalkyl group has 3 to 8 ring members, whereas inother embodiments the number of ring carbon atoms range from 3 to 5, 3to 6, or 3 to 7. Bi- and tricyclic ring systems include both bridgedcycloalkyl groups and fused rings, such as, but not limited to,bicyclo[2.1.1]hexane, adamantyl, decalinyl, and the like. Substitutedcycloalkyl groups may be substituted one or more times with,non-hydrogen and non-carbon groups as defined above. However,substituted cycloalkyl groups also include rings that are substitutedwith straight or branched chain alkyl groups as defined above.Representative substituted cycloalkyl groups may be mono-substituted orsubstituted more than once, such as, but not limited to, 2,2-, 2,3-,2,4-2,5- or 2,6-disubstituted cyclohexyl groups, which may besubstituted with substituents such as those listed above.

Cycloalkylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to acycloalkyl group as defined above. In some embodiments, cycloalkylalkylgroups have from 4 to 16 carbon atoms, 4 to 12 carbon atoms, andtypically 4 to 10 carbon atoms. Substituted cycloalkylalkyl groups maybe substituted at the alkyl, the cycloalkyl or both the alkyl andcycloalkyl portions of the group. Representative substitutedcycloalkylalkyl groups may be mono-substituted or substituted more thanonce, such as, but not limited to, mono-, di- or tri-substituted withsubstituents such as those listed above.

Alkenyl groups include straight and branched chain alkyl groups asdefined above, except that at least one double bond exists between twocarbon atoms. Alkenyl groups have from 2 to 12 carbon atoms, andtypically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group hasone, two, or three carbon-carbon double bonds. Examples include, but arenot limited to vinyl, allyl, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂,—C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, among others. Representativesubstituted alkenyl groups may be mono-substituted or substituted morethan once, such as, but not limited to, mono-, di- or tri-substitutedwith substituents such as those listed above.

Cycloalkenyl groups include cycloalkyl groups as defined above, havingat least one double bond between two carbon atoms. In some embodimentsthe cycloalkenyl group may have one, two or three double bonds but doesnot include aromatic compounds. Cycloalkenyl groups have from 4 to 14carbon atoms, or, in some embodiments, 5 to 14 carbon atoms, 5 to 10carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples ofcycloalkenyl groups include cyclohexenyl, cyclopentenyl,cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl.

Cycloalkenylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of the alkyl group is replaced with a bond to acycloalkenyl group as defined above. Substituted cycloalkenylalkylgroups may be substituted at the alkyl, the cycloalkenyl or both thealkyl and cycloalkenyl portions of the group. Representative substitutedcycloalkenylalkyl groups may be substituted one or more times withsubstituents such as those listed above.

Alkynyl groups include straight and branched chain alkyl groups asdefined above, except that at least one triple bond exists between twocarbon atoms. Alkynyl groups have from 2 to 12 carbon atoms, andtypically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2to 6, or 2 to 4 carbon atoms. In some embodiments, the alkynyl group hasone, two, or three carbon-carbon triple bonds. Examples include, but arenot limited to —C≡CH, —CC≡CH₃, —CH₂C≡CCH₃, —C≡CCH₂CH(CH₂CH₃)₂, amongothers. Representative substituted alkynyl groups may bemono-substituted or substituted more than once, such as, but not limitedto, mono-, di- or tri-substituted with substituents such as those listedabove.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Aryl groups herein include monocyclic, bicyclic andtricyclic ring systems. Thus, aryl groups include, but are not limitedto, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl,anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In someembodiments, aryl groups contain 6-14 carbons, and in others from 6 to12 or even 6-10 carbon atoms in the ring portions of the groups. In someembodiments, the aryl groups are phenyl or naphthyl. Although the phrase“awl groups” includes groups containing fused rings, such as fusedaromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, andthe like), it does not include aryl groups that have other groups, suchas alkyl or halo groups, bonded to one of the ring members. Rather,groups such as tolyl are referred to as substituted aryl groups.Representative substituted aryl groups may be mono-substituted orsubstituted more than once. For example, monosubstituted aryl groupsinclude, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenylor naphthyl groups, which may be substituted with substituents such asthose listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogen orcarbon bond of an alkyl group is replaced with a bond to an aryl groupas defined above. In some embodiments, aralkyl groups contain 7 to 16carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Substitutedaralkyl groups may be substituted at the alkyl, the aryl or both thealkyl and aryl portions of the group. Representative aralkyl groupsinclude but are not limited to benzyl and phenethyl groups and fused(cycloalkylaryl)alkyl groups such as 4-indanylethyl. Representativesubstituted aralkyl groups may be substituted one or more times withsubstituents such as those listed above.

Heterocyclyl groups include aromatic (also referred to as heteroaryl)and non-aromatic ring compounds containing 3 or more ring members, ofwhich one or more is a heteroatom such as, but not limited to, N, O, andS. In some embodiments, the heterocyclyl group contains 1, 2, 3 or 4heteroatoms. In some embodiments, heterocyclyl groups include mono-, bi-and tricyclic rings having 3 to 16 ring members, whereas other suchgroups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members.Heterocyclyl groups encompass aromatic, partially unsaturated andsaturated ring systems, such as, for example, imidazolyl, imidazolinyland imidazolidinyl groups. The phrase “heterocyclyl group” includesfused ring species including those comprising fused aromatic andnon-aromatic groups, such as, for example, benzotriazolyl,2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase alsoincludes bridged polycyclic ring systems containing a heteroatom suchas, but not limited to, quinuclidyl. However, the phrase does notinclude heterocyclyl groups that have other groups, such as alkyl, oxoor halo groups, bonded to one of the ring members. Rather, these arereferred to as “substituted heterocyclyl groups”. Heterocyclyl groupsinclude, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl,tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl,imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl,thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl,thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane,dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl,pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl,dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl,isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl,benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl,benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl,benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl,benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl(azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl,quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl,pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl,dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl,tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl,tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl,tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, andtetrahydroquinolinyl groups. Representative substituted heterocyclylgroups may be mono-substituted or substituted more than once, such as,but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-,5-, or 6-substituted, or disubstituted with various substituents such asthose listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. Heteroaryl groups include, but are not limited to,groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl(pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl(azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl,benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl,adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fusedring compounds in which all rings are aromatic such as indolyl groupsand include fused ring compounds in which only one of the rings isaromatic, such as 2,3-dihydro indolyl groups. Although the phrase“heteroaryl groups” includes fused ring compounds, the phrase does notinclude heteroaryl groups that have other groups bonded to one of thering members, such as alkyl groups. Rather, heteroaryl groups with suchsubstitution are referred to as “substituted heteroaryl groups.”Representative substituted heteroaryl groups may be substituted one ormore times with various substituents such as those listed above.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheterocyclyl group as defined above. Substituted heterocyclylalkylgroups may be substituted at the alkyl, the heterocyclyl or both thealkyl and heterocyclyl portions of the group. Representativeheterocyclyl alkyl groups include, but are not limited to,morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl,pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl.Representative substituted heterocyclylalkyl groups may be substitutedone or more times with substituents such as those listed above.

Heteroaralkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above. Substituted heteroaralkyl groups maybe substituted at the alkyl, the heteroaryl or both the alkyl andheteroaryl portions of the group. Representative substitutedheteroaralkyl groups may be substituted one or more times withsubstituents such as those listed above.

Groups described herein having two or more points of attachment (i.e.,divalent, trivalent, or polyvalent) within the compound of the presenttechnology are designated by use of the suffix, “ene.” For example,divalent alkyl groups are alkylene groups, divalent aryl groups arearylene groups, divalent heteroaryl groups are divalent heteroarylenegroups, and so forth. Substituted groups having a single point ofattachment to the compound of the present technology are not referred tousing the “ene” designation. Thus, e.g., chloroethyl is not referred toherein as chloroethylene.

Alkoxy groups are hydroxyl groups (—OH) in which the bond to thehydrogen atom is replaced by a bond to a carbon atom of a substituted orunsubstituted alkyl group as defined above. Examples of linear alkoxygroups include but are not limited to methoxy, ethoxy, propoxy, butoxy,pentoxy, hexoxy, and the like. Examples of branched alkoxy groupsinclude but are not limited to isopropoxy, sec-butoxy, tert-butoxy,isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groupsinclude but are not limited to cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, and the like. Representative substitutedalkoxy groups may be substituted one or more times with substituentssuch as those listed above.

The terms “alkanoyl” and “alkanoyloxy” as used herein can refer,respectively, to C(O)-alkyl and —O—C(O)-alkyl groups, where in someembodiments the alkanoyl or alkanoyloxy groups each contain 2-5 carbonatoms. Similarly, the terms “aryloyl” and “aryloyloxy” respectivelyrefer to —C(O)-aryl and —O—C(O)-aryl groups.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, asubstituted or unsubstituted aryl group bonded to an oxygen atom and asubstituted or unsubstituted aralkyl group bonded to the oxygen atom atthe alkyl. Examples include but are not limited to phenoxy, naphthyloxy,and benzyloxy. Representative substituted aryloxy and arylalkoxy groupsmay be substituted one or more times with substituents such as thoselisted above.

The term “carboxylic acid” as used herein refers to a compound with a—C(O)OH group. The term “carboxylate” as used herein refers to a —C(O)O⁻group. A “substituted carboxylate” refers to a —C(O)O-G where G is acarboxylate protecting group. Carboxylate protecting groups are wellknown to one of ordinary skill in the art. An extensive list ofprotecting groups for the carboxylate group functionality may be foundin Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G.M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999) which can beadded or removed using the procedures set forth therein and which ishereby incorporated by reference in its entirety and for any and allpurposes as if fully set forth herein.

The term “ester” as used herein refers to —COOR⁷⁰ groups. R⁷⁰ is asubstituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl,aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR⁷¹R⁷², and —NR⁷¹C(O)R⁷² groups, respectively. R⁷¹ and R⁷² areindependently hydrogen, or a substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl orheterocyclyl group as defined herein. Amido groups therefore include butare not limited to carbamoyl groups (—C(O)NH₂) and formamide groups(—NHC(O)H). In some embodiments, the amide is —NR⁷¹C(O)—(C₁₋₅ alkyl) andthe group is termed “carbonylamino,” and in others the amide is—NHC(O)-alkyl and the group is termed “alkanoylamino.”

The term “nitrile” or “cyano” as used herein refers to the —CN group.

Urethane groups include N- and O-urethane groups, i.e., —NR⁷³C(O)OR⁷⁴and —OC(O)NR⁷³R⁷⁴ groups, respectively. R⁷³ and R⁷⁴ are independently asubstituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, awl,aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R⁷³may also be H.

The term “amine” (or “amino”) as used herein refers to —NR⁷⁵R⁷⁶ groups,wherein R⁷⁵ and R⁷⁶ are independently hydrogen, or a substituted orunsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, awl, aralkyl,heterocyclylalkyl or heterocyclyl group as defined herein. In someembodiments, the amine is alkylamino, dialkylamino, arylamino, oralkylarylamino. In other embodiments, the amine is NH₂, methylamino,dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino,phenylamino, or benzylamino.

The term “sulfonamido” includes S- and N-sulfonamide groups, i.e.,—SO₂NR⁷⁸R⁷⁹ and —NR⁷⁸SO₂R⁷⁹ groups, respectively. R⁷⁸ and R⁷⁹ areindependently hydrogen, or a substituted or unsubstituted alkyl,alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, orheterocyclyl group as defined herein. Sulfonamido groups thereforeinclude but are not limited to sulfamoyl groups (—SO₂NH₂). In someembodiments herein, the sulfonamido is —NHSO₂-alkyl and is referred toas the “alkylsulfonylamino” group.

The term “thiol” refers to —SH groups, while sulfides include —SR⁸⁰groups, sulfoxides include —S(O)R⁸¹ groups, sulfones include —SO₂R⁸²groups, and sulfonyls include —SO₂OR⁸³. R⁸⁰, R⁸¹, R⁸², and R⁸³ are eachindependently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl,alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group asdefined herein. In some embodiments the sulfide is an alkylthio group,—S-alkyl.

The term “urea” refers to —NR⁸⁴—C(O)—NR⁸⁵R⁸⁶ groups. R⁸⁴, R⁸⁵, and R⁸⁶groups are independently hydrogen, or a substituted or unsubstitutedalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, orheterocyclylalkyl group as defined herein.

The term “amidine” refers to —C(NR⁸⁷)NR⁸⁸R⁸⁹ and —NR⁸⁷C(NR⁸⁸)R⁸⁹,wherein R⁸⁷, R⁸⁸, and R⁸⁹ are each independently hydrogen, or asubstituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.

The term “guanidine” refers to —NR⁹⁰C(NR⁹¹)NR⁹²R⁹³, wherein R⁹⁰, R⁹¹,R⁹² and R⁹³ are each independently hydrogen, or a substituted orunsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl,heterocyclyl or heterocyclylalkyl group as defined herein.

The term “enamine” refers to —C(R⁹⁴)═C(R⁹⁵)NR⁹⁶R⁹⁷ and—NR⁹⁴C(R⁹⁵)═C(R⁹⁶)R⁹⁷, wherein R⁹⁴, R⁹⁵, R⁹⁶ and R⁹⁷ are eachindependently hydrogen, a substituted or unsubstituted alkyl,cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl orheterocyclylalkyl group as defined herein.

The term “halogen” or “halo” as used herein refers to bromine, chlorine,fluorine, or iodine. In some embodiments, the halogen is fluorine. Inother embodiments, the halogen is chlorine or bromine.

The term “hydroxyl” as used herein can refer to —OH or its ionized form,—O⁻.

The term “imide” refers to —C(O)NR⁹⁸C(O)R⁹⁹, wherein R⁹⁸ and R⁹⁹ areeach independently hydrogen, or a substituted or unsubstituted alkyl,cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl orheterocyclylalkyl group as defined herein.

The term “imine” refers to —CR¹⁰⁰(NR¹⁰¹) and —N(CR¹⁰⁰R¹⁰¹) groups,wherein R¹⁰⁰ and R¹⁰¹ are each independently hydrogen or a substitutedor unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl,heterocyclyl or heterocyclylalkyl group as defined herein, with theproviso that R¹⁰⁰ and R¹⁰¹ are not both simultaneously hydrogen.

The term “nitro” as used herein refers to an —NO₂ group.

The term “trifluoromethyl” as used herein refers to —CF₃.

The term “trifluoromethoxy” as used herein refers to —OCF₃.

The term “azido” refers to —N₃.

The term “trialkyl ammonium” refers to a —N(alkyl)₃ group. Atrialkylammonium group is positively charged and thus typically has anassociated anion, such as halogen anion.

The term “trifluoromethyldiazirido” refers to

The term “isocyano” refers to —NC.

The term “isothiocyano” refers to —NCS.

The term “pentafluorosulfanyl” refers to —SF₅.

The phrase “selectively treats” as used herein will be understood bypersons of ordinary skill in the art and will vary to some extentdepending upon the context in which the phrase is used. If there areuses of the phrase which are not clear to persons of ordinary skill inthe art, given the context in which the phrase is used, the phrase atminimum refers to the compounds acting through a viral-specificmechanism of action, resulting in fewer off-target effects because thecompounds target the virus and not the host.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the likeinclude the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember. Thus, for example, a group having 1-3 atoms refers to groupshaving 1, 2, or 3 atoms. Similarly, a group having 1-5 atoms refers togroups having 1, 2, 3, 4, or 5 atoms, and so forth.

Pharmaceutically acceptable salts of compounds described herein arewithin the scope of the present technology and include acid or baseaddition salts which retain the desired pharmacological activity and isnot biologically undesirable (e.g., the salt is not unduly toxic,allergenic, or irritating, and is bioavailable). When the compound ofthe present technology has a basic group, such as, for example, an aminogroup, pharmaceutically acceptable salts can be formed with inorganicacids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuricacid, and phosphoric acid), organic acids (e.g. alginate, formic acid,acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid,tartaric acid, lactic acid, maleic acid, citric acid, succinic acid,malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (suchas aspartic acid and glutamic acid). When the compound of the presenttechnology has an acidic group, such as for example, a carboxylic acidgroup, it can form salts with metals, such as alkali and earth alkalimetals (e.g. Na⁺, Li⁺, K⁺, Ca²⁺, Mg²⁺, Zn²⁺), ammonia or organic amines(e.g. dicyclohexylamine, trimethylamine, triethylamine, pyridine,picoline, ethanolamine, diethanolamine, triethanolamine) or basic aminoacids (e.g., arginine, lysine and ornithine). Such salts can be preparedin situ during isolation and purification of the compounds or byseparately reacting the purified compound in its free base or free acidform with a suitable acid or base, respectively, and isolating the saltthus formed.

Those of skill in the art will appreciate that compounds of the presenttechnology may exhibit the phenomena of tautomerism, conformationalisomerism, geometric isomerism and/or stereoisomerism. As the formuladrawings within the specification and claims can represent only one ofthe possible tautomeric, conformational isomeric, stereochemical orgeometric isomeric forms, it should be understood that the presenttechnology encompasses any tautomeric, conformational isomeric,stereochemical and/or geometric isomeric forms of the compounds havingone or more of the utilities described herein, as well as mixtures ofthese various different forms.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The presence and concentrations of theisomeric forms will depend on the environment the compound is found inand may be different depending upon, for example, whether the compoundis a solid or is in an organic or aqueous solution. For example, inaqueous solution, quinazolinones may exhibit the following isomericforms, which are referred to as tautomers of each other:

As another example, guanidines may exhibit the following isomeric formsin protic organic solution, also referred to as tautomers of each other:

Because of the limits of representing compounds by structural formulas,it is to be understood that all chemical formulas of the compoundsdescribed herein represent all tautomeric forms of compounds and arewithin the scope of the present technology.

Stereoisomers of compounds (also known as optical isomers) include allchiral, diastereomeric, and racemic forms of a structure, unless thespecific stereochemistry is expressly indicated. Thus, compounds used inthe present technology include enriched or resolved optical isomers atany or all asymmetric atoms as are apparent from the depictions. Bothracemic and diastereomeric mixtures, as well as the individual opticalisomers can be isolated or synthesized so as to be substantially free oftheir enantiomeric or diastereomeric partners, and these stereoisomersare all within the scope of the present technology.

The compounds of the present technology may exist as solvates,especially hydrates. Hydrates may form during manufacture of thecompounds or compositions comprising the compounds, or hydrates may formover time due to the hygroscopic nature of the compounds. Compounds ofthe present technology may exist as organic solvates as well, includingDMF, ether, and alcohol solvates among others. The identification andpreparation of any particular solvate is within the skill of theordinary artisan of synthetic organic or medicinal chemistry.

The present technology provides compounds expected to inhibit one ormore of enteroviruses, paramyxoviruses, respiratory viruses,flaviviridae viruses, bunyaviridae viruses, togaviridae viruses, andrabies.

Accordingly, in an aspect, a compound represented by Formula I isprovided

or a pharmaceutically acceptable salt thereof. In Formula I, R¹ is H,alkyl, cycloalkyl, aryl, or heteroaryl; R² is a substituted orunsubstituted aryl or heteroaryl; R³ is a substituted or unsubstitutedcycloalkyl, aryl, or heteroaryl; and (a) X¹ is N, Y¹ is N, and Z¹ is CH;or (b) X¹ is N, Y¹ is CH, and Z¹ is N; or (c) X¹ is CH, Y¹ is CH, and Z¹is CH. R¹ may be a substituted or unsubstituted C₁-C₆ alkyl,unsubstituted C₄-C₇ cycloalkyl, or a substituted phenyl group. In any ofthe above embodiments, R² may be a heteroaryl group, preferably asix-membered nitrogen-containing heteroaryl group. In any of the aboveembodiments, R² may be a substituted aryl group where the aryl groupbears 1, 2, or 3 substituents. In any of the above embodiments, R² maybe a substituted aryl group where the substituents are selected from thegroup consisting of a halogen, a nitro group, cyano group, an alkanoylgroup, a carbamoyl group, an ester, an amido, a sulfonyl group, asulfonamido group, and a trifluoromethyl group. In some embodiments, R²is fluorophenyl, difluorophenyl, trifluorophenyl, sulfonamidophenyl, ortrifluormethylphenyl. In some embodiments, R³ is a 2-thiophenyl or3-thiophenyl group.

In any of the above embodiments, the compound of Formula I may be

The present technology provides pharmaceutical compositions andmedicaments comprising any of one of the embodiments of the compounds ofFormula I (or a pharmaceutically acceptable salt thereof) disclosedherein and a pharmaceutically acceptable carrier or one or moreexcipients or fillers. The compositions may be used in the methods andtreatments described herein. The pharmaceutical composition may includean effective amount of any of one of the embodiments of the compounds ofthe present technology disclosed herein. In any of the aboveembodiments, the effective amount may be determined in relation to asubject. “Effective amount” refers to the amount of a compound orcomposition required to produce a desired effect. One example of aneffective amount includes amounts or dosages that yield acceptabletoxicity and bioavailability levels for therapeutic (pharmaceutical) useincluding, but not limited to, the treatment of an enterovirus. Anotherexample of an effective amount includes amounts or dosages that yieldacceptable toxicity and bioavailability levels for therapeutic(pharmaceutical) use including, but not limited to, the prophylaxis ofan enterovirus. Another example of an effective amount includes amountsor dosages that are capable of reducing symptoms associated with anenterovirus, such as, for example, fever, headache, and/or encephalitis.As used herein, a “subject” or “patient” is a mammal, such as a cat,dog, rodent or primate. Typically the subject is a human, and,preferably, a human suffering from or suspected of suffering from anenterovirus, paramyxovirus, respiratory virus, flaviviridae virus,bunyaviridae virus, togaviridae virus, or rabies virus. In anyembodiment disclosed herein, the enterovirus may be Coxsackievirus A9,Coxsackievirus A16, Coxsackievirus B1, Coxsackievirus B2, CoxsackievirusB3-H3, Coxsackievirus B4, Coxsackievirus B5, Enterovirus 68, Enterovirus71, Echovirus 6, Echovirus 7, Echovirus 9, Echovirus 11, Echovirus 18,Echovirus 25, Echovirus 30, Poliovirus 1, or Poliovirus 3. The term“subject” and “patient” can be used interchangeably.

In any of the embodiments of the present technology described herein,the pharmaceutical composition may be packaged in unit dosage form. Theunit dosage form is effective in treating an enterovirus. Generally, aunit dosage including a compound of the present technology will varydepending on patient considerations. Such considerations include, forexample, age, protocol, condition, sex, extent of disease,contraindications, concomitant therapies and the like. An exemplary unitdosage based on these considerations may also be adjusted or modified bya physician skilled in the art. For example, a unit dosage for a patientcomprising a compound of the present technology may vary from 1×10⁻⁴g/kg to 1 g/kg, preferably, 1×10⁻³ g/kg to 1.0 g/kg. Dosage of acompound of the present technology may also vary from 0.01 mg/kg to 100mg/kg or, preferably, from 0.1 mg/kg to 10 mg/kg. Suitable unit dosageforms, include, but are not limited to powders, tablets, pills,capsules, lozenges. suppositories. patches. nasal sprays, injectibles,implantable sustained-release formulations, rnucoadherent films, topicalvarnishes, lipid complexes, etc.

The pharmaceutical compositions may be prepared by mixing one or morecompounds of Formula I, pharmaceutically acceptable salts thereof,stereoisomers thereof, tautomers thereof, or solvates thereof, withpharmaceutically acceptable carriers, excipients, binders, diluents orthe like to prevent and treat disorders associated with the effects ofincreased plasma and/or hepatic lipid levels. The compounds andcompositions described herein may be used to prepare formulations andmedicaments that treat an enterovirus, paramyxovirus, respiratory virus,flaviviridae virus, Bunyaviridae virus, togaviridae virus, or rabies.Such compositions may be in the form of, for example, granules, powders,tablets, capsules, syrup, suppositories, injections, emulsions, elixirs,suspensions or solutions. The instant compositions may be formulated forvarious routes of administration, for example, by oral, parenteral,topical, rectal, nasal, vaginal administration, or via implantedreservoir. Parenteral or systemic administration includes, but is notlimited to, subcutaneous, intravenous, intraperitoneal, andintramuscular, injections. The following dosage forms are given by wayof example and should not be construed as limiting the instant presenttechnology.

For oral, buccal, and sublingual administration, powders, suspensions,granules, tablets, pills, capsules, gelcaps, and caplets are acceptableas solid dosage forms. These can be prepared, for example, by mixing oneor more compounds of the instant present technology, or pharmaceuticallyacceptable salts or tautomers thereof, with at least one additive suchas a starch or other additive. Suitable additives are sucrose, lactose,cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates,chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins,collagens, casein, albumin, synthetic or semi-synthetic polymers orglycerides. Optionally, oral dosage forms can contain other ingredientsto aid in administration, such as an inactive diluent, or lubricantssuch as magnesium stearate, or preservatives such as paraben or sorbicacid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, adisintegrating agent, binders, thickeners, buffers, sweeteners,flavoring agents or perfuming agents. Tablets and pills may be furthertreated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form ofpharmaceutically acceptable emulsions, syrups, elixirs, suspensions, andsolutions, which may contain an inactive diluent, such as water.Pharmaceutical formulations and medicaments may be prepared as liquidsuspensions or solutions using a sterile liquid, such as, but notlimited to, an oil, water, an alcohol, and combinations of these.Pharmaceutically suitable surfactants, suspending agents, emulsifyingagents, may be added for oral or parenteral administration.

As noted above, suspensions may include oils. Such oils include, but arenot limited to, peanut oil, sesame oil, cottonseed oil, corn oil andolive oil. Suspension preparation may also contain esters of fatty acidssuch as ethyl oleate, isopropyl myristate, fatty acid glycerides andacetylated fatty acid glycerides. Suspension formulations may includealcohols, such as, but not limited to, ethanol, isopropyl alcohol,hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as butnot limited to, poly(ethyleneglycol), petroleum hydrocarbons such asmineral oil and petrolatum; and water may also be used in suspensionformulations.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which may be prepared using a suitable dispersant or wettingagent and a suspending agent. Injectable forms may be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils may be employed as solvents or suspendingagents. Typically, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the pharmaceutical formulation and/or medicament may be apowder suitable for reconstitution with an appropriate solution asdescribed above. Examples of these include, but are not limited to,freeze dried, rotary dried or spray dried powders, amorphous powders,granules, precipitates, or particulates. For injection, the formulationsmay optionally contain stabilizers, pH modifiers, surfactants,bioavailability modifiers and combinations of these.

Compounds of the present technology may be administered to the lungs byinhalation through the nose or mouth. Suitable pharmaceuticalformulations for inhalation include solutions, sprays, dry powders, oraerosols containing any appropriate solvents and optionally othercompounds such as, but not limited to, stabilizers, antimicrobialagents, antioxidants, pH modifiers, surfactants, bioavailabilitymodifiers and combinations of these. The carriers and stabilizers varywith the requirements of the particular compound, but typically includenonionic surfactants (Tweens, Pluronics, or polyethylene glycol),innocuous proteins like serum albumin, sorbitan esters, oleic acid,lecithin, amino acids such as glycine, buffers, salts, sugars or sugaralcohols. Aqueous and nonaqueous (e.g., in a fluorocarbon propellant)aerosols are typically used for delivery of compounds of the presenttechnology by inhalation.

Dosage forms for the topical (including buccal and sublingual) ortransdermal administration of compounds of the present technologyinclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, and patches. The active component may be mixed under sterileconditions with a pharmaceutically-acceptable carrier or excipient, andwith any preservatives, or buffers, which may be required. Powders andsprays can be prepared, for example, with excipients such as lactose,talc, silicic acid, aluminum hydroxide, calcium silicates and polyimidepowder, or mixtures of these substances. The ointments, pastes, creamsand gels may also contain excipients such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof. Absorption enhancers can also be used toincrease the flux of the compounds of the present technology across theskin. The rate of such flux can be controlled by either providing a ratecontrolling membrane (e.g., as part of a transdermal patch) ordispersing the compound in a polymer matrix or gel.

Besides those representative dosage forms described above,pharmaceutically acceptable excipients and carriers are generally knownto those skilled in the art and are thus included in the instant presenttechnology. Such excipients and carriers are described, for example, in“Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991),which is incorporated herein by reference.

The formulations of the present technology may be designed to beshort-acting, fast-releasing, long-acting, and sustained-releasing asdescribed below. Thus, the pharmaceutical formulations may also beformulated for controlled release or for slow release.

The instant compositions may also comprise, for example, micelles orliposomes, or some other encapsulated form, or may be administered in anextended release form to provide a prolonged storage and/or deliveryeffect. Therefore, the pharmaceutical formulations and medicaments maybe compressed into pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections or as implants such as stents. Suchimplants may employ known inert materials such as silicones andbiodegradable polymers.

Specific dosages may be adjusted depending on conditions of disease, theage, body weight, general health conditions, sex, and diet of thesubject, dose intervals, administration routes, excretion rate, andcombinations of drugs. Any of the above dosage forms containingeffective amounts are well within the bounds of routine experimentationand therefore, well within the scope of the instant present technology.

Various assays and model systems can be readily employed to determinethe therapeutic effectiveness of the treatment according to the presenttechnology.

For each of the indicated conditions described herein, test subjectswill exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75-90%,or 95% or greater, reduction, in one or more symptom(s) caused by, orassociated with, the disorder in the subject, compared toplacebo-treated or other suitable control subjects.

In an aspect, a method for inhibiting the replication of an enterovirus,paramyxovirus, respiratory virus, flaviviridae virus, bunyaviridaevirus, togaviridae virus, or rabies virus in a cell infected with theenterovirus, paramyxovirus, respiratory virus, flaviviridae virus,bunyaviridae virus, togaviridae virus, or rabies virus is provided. Themethod includes contacting an effective amount of any one of the aboveembodiments of compounds of Formula I (or a pharmaceutically acceptablesalt thereof) with the cell infected with the enterovirus,paramyxovirus, respiratory virus, flaviviridae virus, bunyaviridaevirus, togaviridae virus, or rabies virus, thereby inhibiting thereplication of the enterovirus, paramyxovirus, respiratory virus,flaviviridae virus, bunyaviridae virus, togaviridae virus, or rabiesvirus in the cell. The enterovirus may be Coxsackievirus A9,Coxsackievirus A16, Coxsackievirus B1, Coxsackievirus B2, CoxsackievirusB3-H3, Coxsackievirus B4, Coxsackievirus B5, Enterovirus 68 (also knownas Enterovirus D68), Enterovirus 71, Echovirus 6, Echovirus 7, Echovirus9, Echovirus 11, Echovirus 18, Echovirus 25, Echovirus 30, Poliovirus 1,or Poliovirus 3. The contacting step may include administration of apharmaceutical composition, where the pharmaceutical compositionincludes an effective amount of any one of the embodiments of thecompounds of Formula I (or a pharmaceutically acceptable salt thereof)and a pharmaceutically acceptable carrier. The effective amount may befrom about 0.01 μg to about 1 mg of the compound per gram of thecomposition, and preferably from about 0.1 μg to about 500 μg of thecompound per gram of the composition.

In an aspect, a method of inhibiting death of a cell infected with anenterovirus, paramyxovirus, respiratory virus, flaviviridae virus,bunyaviridae virus, togaviridae virus, or rabies virus, the methodcomprising contacting an effective amount of any one of the aboveembodiments of the compounds of Formula I (or a pharmaceuticallyacceptable salt thereof) with the cell infected with the enterovirus,paramyxovirus, respiratory virus, flaviviridae virus, bunyaviridaevirus, togaviridae virus, or rabies virus, thereby inhibiting the deathof the cell. The enterovirus may be Coxsackievirus A9, CoxsackievirusA16, Coxsackievirus B1, Coxsackievirus B2, Coxsackievirus B3-H3,Coxsackievirus B4, Coxsackievirus B5, Enterovirus 68 (also known asEnterovirus D68), Enterovirus 71, Echovirus 6, Echovirus 7, Echovirus 9,Echovirus 11, Echovirus 18, Echovirus 25, Echovirus 30, Poliovirus 1, orPoliovirus 3. The contacting step may include administration of apharmaceutical composition, where the pharmaceutical compositionincludes an effective amount of any one of the embodiments of thecompounds of Formula I (or a pharmaceutically acceptable salt thereof)and a pharmaceutically acceptable carrier. The effective amount may befrom about 0.01 μg to about 1 mg of the compound per gram of thecomposition, and preferably from about 0.1 μg to about 500 μg of thecompound per gram of the composition.

In an aspect, a method of treating a patient or animal infected with anenterovirus, paramyxovirus, respiratory virus, flaviviridae virus,bunyaviridae virus, togaviridae virus, or rabies virus is provided, themethod including administration of an effective amount of a compound ofany one of the above embodiments of the present technology to thepatient or animal. In the method, administration of the effective amountof a compound of any one of the above embodiments of the presenttechnology to the patient or animal treats the patient or animalinfected with the enterovirus, paramyxovirus, respiratory virus,flaviviridae virus, bunyaviridae virus, togaviridae virus, or rabiesvirus. The enterovirus may be Coxsackievirus A9, Coxsackievirus A16,Coxsackievirus B1, Coxsackievirus B2, Coxsackievirus B3-H3,Coxsackievirus B4, Coxsackievirus B5, Enterovirus 68 (also known asEnterovirus D68), Enterovirus 71, Echovirus 6, Echovirus 7, Echovirus 9,Echovirus 11, Echovirus 18, Echovirus 25, Echovirus 30, Poliovirus 1, orPoliovirus 3. It may be that administration of the effective amount ofthe compound of any one of the above embodiments of the presenttechnology selectively treats the enterovirus, paramyxovirus,respiratory virus, flaviviridae virus, bunyaviridae virus, togaviridaevirus, or rabies virus.

In any of the embodiments of the method of treating a patient or animalinfected with an enterovirus, paramyxovirus, respiratory virus,flaviviridae virus, bunyaviridae virus, togaviridae virus, or rabiesvirus, the method may include administration of a pharmaceuticalcomposition, where the pharmaceutical composition includes an effectiveamount of any one of the embodiments of the compounds of the presenttechnology or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier. The enterovirus may beCoxsackievirus A9, Coxsackievirus A16, Coxsackievirus B1, CoxsackievirusB2, Coxsackievirus B3-H3, Coxsackievirus B4, Coxsackievirus B5,Enterovirus 68 (also known as Enterovirus D68), Enterovirus 71,Echovirus 6, Echovirus 7, Echovirus 9, Echovirus 11, Echovirus 18,Echovirus 25, Echovirus 30, Poliovirus 1, or Poliovirus 3. The effectiveamount may be from about 0.01 μg to about 1 mg of the compound per gramof the composition, and preferably from about 0.1 μg to about 500 μg ofthe compound per gram of the composition. In any of the embodiments ofthe method, the compound or composition may be administered orally,parenterally, rectally, or transdermally.

The examples herein are provided to illustrate advantages of the presenttechnology and to further assist a person of ordinary skill in the artwith preparing or using the compounds of the present technology orsalts, pharmaceutical compositions, derivatives, metabolites, prodrugs,racemic mixtures or tautomeric forms thereof. The examples herein arealso presented in order to more fully illustrate the preferred aspectsof the present technology. The examples should in no way be construed aslimiting the scope of the present technology, as defined by the appendedclaims. The examples can include or incorporate any of the variations,aspects or aspects of the present technology described above. Thevariations, aspects or aspects described above may also further eachinclude or incorporate the variations of any or all other variations,aspects or aspects of the present technology.

EXAMPLES

Compounds of the present technology may be synthesized by syntheticmedicinal chemistry procedures well known to one of ordinary skill inthe art. The compounds of the present technology may be purified bynormal synthetic medicinal chemistry procedures, usually columnchromatography and their structures determined by high field NMRspectroscopy. Exemplary procedures and methods include, but are notlimited to, those described and referenced in U.S. Pat. Publ. No.2015/0164910.

Biological Testing of Representative Compounds of the Present Technology

Virus Cytopathic Effect Assay:

Cells growing in 96 well plates are infected with a given virus at givenlow multiplicities of infection pre-determined to result in 100%cytopathic effects (CPE) in the cultures after 3-4 days incubation.Cultures are monitored daily for microscopic signs of typical CPE:rounding of cells and detachment. When CPE appears maximal in thecontrol wells without the antiviral compounds, the cells are fixed with4% formaldehyde before staining with 0.25% crystal violet solution. Deadcells and debris are washed out and the remaining blue stain intensityin each well is quantified by spectrophotometry at a wavelength of 590nm (OD₅₉₀) as a measurement of viability.

In Vitro Evaluation of Antiviral Activities:

Each compound is initially tested against each virus at 10 μM in a virusCPE assay. A compound that is active against a virus, protecting thecells from CPE, is further evaluated for its 50% effective concentration(EC₅₀) value and 50% cytotoxicity concentration (CC₅₀) value. Serial2-fold dilutions of an active compound are prepared. For EC₅₀ valuedetermination, a 7-point dose-response curve is constructed using avirus CPE assay and EC₅₀ value is estimated using four parameter modelor sigmoidal model. For CC₅₀ value determination, cells are incubatedwith serial 2-fold dilutions of a compound for the same period as thevirus CPE assay, and then cells were fixed, stained and read as in thevirus CPE assay.

Exemplary In Vitro Evaluation of Anti-Rabies Activity:

T-150 flasks of confluent BHK-21 cells are prepared and subsequentlytrypsinized and made into cell suspensions. 50 μL of a 5×10⁵ cells/mLcell suspension (25,000 cells/well) are loaded into each well of a96-well, white walled, clear bottom cell culture plate, with theexception of row H which is reserved for Media only (see Scheme 2below). Concentrations of double the final intended concentration (“2×Drug”) of the well are made with the antivirals (Isoprinosine and testcompounds). At least 6 concentration points are usually performed. Add100 μL per well that will be tested for effective concentration (“drugwells”) and cytotoxic concentration (“tox wells”). The rabies virus isdiluted 1:1000 and 50 μL of this dilution is added per well in the drugwells and virus control wells. Additional media is added to the tox,Control, Virus Control, and Media only wells to ensure the final volumeis 200 μL—e.g., tox wells should be 100 μL 2× Drug, 50 μL cells (5×10⁵cells/mL), and 50 μL media; Media only wells (row H of Scheme 2) shouldbe 200 μl media. The 96 well plates are then covered and incubated for 5days at 37° C. in a 5% CO₂ atmosphere. Upon completion of the 5-dayincubation period, the well plate is visually checked to determine thedifference in the Control wells and Virus Control wells as well as anyvisible toxicity from the compounds. A Promega CellTiter-Glo LuminescentCell Viability Assay is then performed using the Fluoroskan FL to scanfor luminescence.

Scheme 2.

1 2 3 4 5 6 7 8 9 10 11 12 A Drug 1 Drug 1 Drug 1 Drug 1 Drug 1 Drug 1Drug 2 Drug 2 Drug 2 Drug 2 Drug 2 Drug 2 B 1000 μM 333 μM 111 μM 37 μM12.3 μM 4 μM 100 μM 33 μM 11 μM 3.7 μM 1.2 μM 0.4 μM C D Cells + 150 μlmedia Cells + virus + 100 μl media Cells + 150 μl media Cells + virus +100 μl media (Control) (Virus control) (Control) (Virus control) E Tox 1Tox 1 Tox 1 Tox 1 Tox 1 Tox 1 Tox 2 Tox 2 Tox 2 Tox 2 Tox 2 Tox 2 F 1000μM 333 μM 111 μM 37 μM 12.3 μM 4 μM 100 μM 33.3 μM 11.1 μM 3.7 μM 1.2 μM0.4 μM G H Media only Media only Drug = 100 μl 2× drug, 50 μl cells (5e5cells/ml), 50 μl virus (1:1000) Tox = 100 μl 2× drug, 50 μl cells (5e5cells/ml), 50 μl media

Cell-based assays evaluating the antiviral activities of compounds ofthe present technology with certain enteroviruses, paramyxoviruses,respiratory viruses, flaviviridae viruses, bunyaviridae viruses,togaviridae viruses, and rabies viruses may be compared to positivecontrols. One such positive control is JX-001, the structure of which isillustrated below.

Compounds of Formula I are expected to inhibit one or more ofenteroviruses, paramyxoviruses, respiratory viruses, flaviviridaeviruses, bunyaviridae viruses, togaviridae viruses, and rabies viruses.

Tables 1 and 2 provide the results of evaluating the antiviralactivities of certain representative compounds of the present technologywith certain enteroviruses. The data in Tables 1 and 2 are EC₅₀ valuesin μM units. Abbreviations are as follows:

CVB3-H3: Coxsackievirus B3-H3

PV1: Poliovirus 1

PV3: Poliovirus 3

CVB1: Coxsackievirus B1

CVB2: Coxsackievirus B2

CVB4: Coxsackievirus B4

CVB5: Coxsackievirus B5

EV71: Enterovirus 71

COX A9: Coxsackievirus A9

ECHO06: Echovirus 6

ECHO07: Echovirus 7

ECHO09: Echovirus 9

ECHO11: Echovirus 11

ECHO25: Echovirus 25

ECHO30: Echovirus 30

TABLE 1 Evaluation of Compounds of the Present Technology AgainstEnteroviruses Compound (JX #) CVB3-H3 PV1 PV3 CVB1 CVB2 CVB4 CVB5 JX-0011.4 ± 0.6 7 ± 0.0 7 ± 0.0 2.4 ± 0.2 2.8 ± 0.4 2.3 ± 0.0 2.3 ± 0.0JX-035 >10 >10 >10 >10 >10 >10 >10 JX-036 >10 >10 >10 >10 >10 >10 >10JX-037 3.1 ± 0.1 >25 >25 3.6 ± 0.6 3.6 ± 0.6 3.1 ± 0.1 2.7 ± 0.6 JX-0621.3 >10 >10 1.2 1.2 1.2 1.2 JX-063 >10 >10 >10 >10 >10 >10 >10 JX-0722.2 ± 0.4 >10 >10 1.56 2.33 1. In Vitro antiviral testing was done inHeLa-RW cells. 2. x.x ± x.x: mean ± standard deviation (sd). EC₅₀ valuesof single experiments are shown as x.x. 3. >10 and >25 entries:compounds were tested in 10 μM or 25 μM, respectively, and no antiviralactivities were observed. 4. TBD: A compound is active against anenteroviral infection in 10 μM concentration; EC₅₀ not yet determined.

TABLE 2 Evaluation of Compounds of the Present Technology AgainstEnteroviruses (cont.) Compound (JX #) EV71 COX A9 ECHO06 ECHO07 ECHO09ECHO11 ECHO25 ECHO30 JX-001 2.3 ± 1.2 2.6 ± 0.9 2.3 ± 0.9 2.4 2.1 ± 1.21.5 ± 0.4 3 1.2 JX-035 >10 >10 >10 >10 >10 >10 >10 >10JX-036 >10 >10 >10 >10 >10 >10 >10 >10 JX-037 2.2 JX-062 0.8 TBD TBD TBD0.4 1.2 TBD TBD JX-063 TBD TBD TBD TBD TBD TBD TBD TBD JX-072 1.2 TBDTBD 3 TBD TBD TBD TBD 1. In Vitro antiviral testing was done in LLCcells. 2. x.x ± x.x: mean ± standard deviation (sd). EC₅₀ values ofsingle experiments are shown as x.x. 3. >10 and >25 entries: compoundswere tested in 10 μM or 25 μM, respectively, and no antiviral activitieswere observed. 4. TBD: A compound is active against an enteroviralinfection in 10 μM concentration; EC₅₀ not yet determined.

-   -   5. A blank cell indicates that the referenced compound has not        yet been tested with the indicated enterovirus.

Table 3 provides the compound concentration in μM units that reducescell viability of the host cell by 50% (CC₅₀) for certain compounds ofthe present technology for HeLa-RW and LLC cells. Blank cells indicatethat the cytotoxicity assessment is not yet complete.

TABLE 3 Evaluation of CC₅₀ of Compounds of the Present TechnologyCompound (JX #) HeLa-RW LLC JX-001 12.5 50 JX-037 >200 100 JX-062 18 25JX-072 18.8 >200

Table 4 provides the results of cell-based assays with RD cellsevaluating the antiviral activities of certain representative compoundsof the present technology with certain strains of Enterovirus D68,namely strains Fermon (“D68/Fermon”), US/Mo/14-18949(“D68/US/Mo/14-18949”), and US/KY/14-18953 (“D68/US/KY/14-18953”). Thevalues indicated in the strain columns are EC₅₀ values in μM units. TheCC₅₀ values (in μM units) for RD cells are also provided for evaluationof SI₅₀.

TABLE 4 Evaluation of Activities of Compounds of the Present TechnologyAgainst strains of Enterovirus D68 Compound CC₅₀ (JX #) FermonUS/Mo/14-18949 US/KY/14-18953 (RD) JX-001 0.35 ± 0.05 0.33 ± 0.05 0.50 ±0.17 200 JX-037 0.86 ± 0.31 0.57 ± 0.15 1.1 ± 0.3 >200 JX-062 0.16 ±0.03 0.13 ± 0.03 0.26 ± 0.07 25 JX-072 <0.4 0.6 25 1. In Vitro antiviraltesting was done in RD cells. 2. x.x ± x.x: mean ± standard deviation(sd). EC₅₀ values of single experiments are shown as x.x. EC₅₀ values ofa few experiments are listed out as a series of values. 3. A blank cellindicates that the referenced compound has not yet been tested with theindicated Enterovirus D68 strain.

The data for the strains provided in these examples illustrate that thecompounds of the present technology have high activity whileconcurrently exhibiting excellent SI values. For example, JX-037,JX-062, and JX-072 each have at least one strain against which thecompound has an EC₅₀ less than 1 μM while concurrently having a SIgreater than 25. As a further example, for the 2014 epidemic strain ofEnterovirus D68/US/Mo/14-18949, JX-037 has an SI of over 350(>200/0.57=>350).

Exemplary Mouse Studies of Inhibition of Viruses

Compound Preparation and Dosing:

Compounds will be formulated with an appropriate vehicle for the study,such as a suspension in a 0.5% xanthan gum-1% Tween 80 vehicle. Thecompound will be administered intragastrically with a 0.5-ml Glaspaksyringe fitted with a 24-gauge feeding needle (Popper and Sons, Inc.,New York, N.Y.).

Infection of Suckling Mice:

Newborn ICR mouse pups of both sexes (weight, 1.2 to 1.9 g), born within24 h of receipt, will obtained with their dams. The pups will be pooled,weighed, and distributed to the nursing dams in groups of 10. Threecages (30 pups) will be included for each dosage group. Each mouse pupwill infected subcutaneously over the right shoulder within 24 h ofbirth with the virus. The amount of virus inoculated will be titrated toproduce approximately 80% mortality in untreated animals over the 13-dayobservation period. The compound of interest will be administered as asingle, 0.03-ml dose 2.5 days postinfection. Mouse pups will be checkeddaily for evidence of paralysis or death (paralyzed animals will bekilled). It is expected that a suitable dosage of compounds of thepresent technology will be determined that will enable at least eightypercent of treated virus-infected animals to survive the entire 14-dayobservation period.

REFERENCES

-   1. Cherry, J. D., Krogstad P. K., Enteroviruses and Parechoviruses,    in Textbook of Pediatric Infectious Diseases, R. D. Feigin, et al.,    Editors. 2009, WB Saunders Co: Philadelphia, Pa. p. 1984-2041.-   2. a) McMinn, P., et al., Neurological manifestations of enterovirus    71 infection in children during an outbreak of hand, foot, and mouth    disease in Western Australia. Clin Infect Dis, 2001. 32(2): p.    236-42. b) McMinn, P. C., An overview of the evolution of    enterovirus 71 and its clinical and public health significance. FEMS    Microbiol Rev, 2002. 26(1): p. 91-107.-   3. Seiff, A., Cambodia unravels cause of mystery illness.    Lancet, 2012. 380(9838): p. 206.-   4. a) Verma, N. A., et al., Outbreak of life-threatening    coxsackievirus B1 myocarditis in neonates. Clin Infect Dis, 2009.    49(5): p. 759-63. b) Wikswo, M. E., et al., Increased activity of    Coxsackievirus B1 strains associated with severe disease among young    infants in the United States, 2007-2008. Clin Infect Dis, 2009.    49(5): p. e44-51.-   5. a) Notes from the field: severe hand, foot, and mouth disease    associated with coxsackievirus A6-Alabama, Connecticut, California,    and Nevada, November 2011-February 2012. MMWR Morb Mortal Wkly    Rep, 2012. 61(12): p. 213-4. b) Flett, K., et al., Hand, foot, and    mouth disease caused by coxsackievirus a6. Emerg Infect Dis, 2012.    18(10): p. 1702-4. c) Mathes, E. F., et al., “Eczema Coxsackium” and    Unusual Cutaneous Findings in an Enterovirus Outbreak. Pediatrics,    2013.-   6. a) Nonpolio enterovirus and human parechovirus    surveillance—United States, 2006-2008. MMWR Morb Mortal Wkly    Rep, 2010. 59(48): p. 1577-80. b) Progress toward interruption of    wild poliovirus transmission-worldwide, january 2011-march 2012.    MMWR Morb Mortal Wkly Rep, 2012. 61: p. 353-7. c) De Palma, A. M.,    et al., Selective inhibitors of picornavirus replication. Med Res    Rev, 2008. 28(6): p. 823-84.-   7. Pamukcu, R.; Piazza, G. A. U.S. Pat. No. 5,942,520, 24 Aug. 1999.-   8. a) MacKy, M.; Nortcliffe, A.; McNab, H.; Hulme, A. N. Gas-Phase    Synthesis of Pyrazolo[3,4-b]pyridin-4-ones Synthesis (2015), 47(2),    242-248. b) Ji, N.; Meredith, E.; Liu, D.; Adams, C. M.; Artman, G.    D., III; Jendza, K. C.; Ma, F.; Mainolfi, N.; Powers, J. J.;    Zhang, C. Synthesis of 1-substituted-3-aminopyrazoles Tetrahedron    Letters (2010), 51(52), 6799-6801.-   9. Chen, H. et al. (2014); Knerr, L.; Aakerud, T.; Hallberg, K.;    Oester, L.; Rohman, M.; Oesterlund, K.; Beisel, H.-G.; Olsson, T.;    Brengdhal, J. et al. Discovery of a novel pyrazole series of group X    secreted phospholipase A2 inhibitor (sPLA2X) via fragment based    virtual screening Bioorganic & Medicinal Chemistry Letters (2014),    24(22), 5251-5255.

While certain embodiments have been illustrated and described, a personwith ordinary skill in the art, after reading the foregoingspecification, can effect changes, substitutions of equivalents andother types of alterations to the compounds of the present technology orsalts, pharmaceutical compositions, derivatives, prodrugs, metabolites,tautomers or racemic mixtures thereof as set forth herein. Each aspectand embodiment described above can also have included or incorporatedtherewith such variations or aspects as disclosed in regard to any orall of the other aspects and embodiments.

The present technology is also not to be limited in terms of theparticular aspects described herein, which are intended as singleillustrations of individual aspects of the present technology. Manymodifications and variations of this present technology can be madewithout departing from its spirit and scope, as will be apparent tothose skilled in the art. Functionally equivalent methods within thescope of the present technology, in addition to those enumerated herein,will be apparent to those skilled in the art from the foregoingdescriptions. Such modifications and variations are intended to fallwithin the scope of the appended claims. It is to be understood thatthis present technology is not limited to particular methods, reagents,compounds, compositions, labeled compounds or biological systems, whichcan, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only,and is not intended to be limiting. Thus, it is intended that thespecification be considered as exemplary only with the breadth, scopeand spirit of the present technology indicated only by the appendedclaims, definitions therein and any equivalents thereof.

The embodiments, illustratively described herein may suitably bepracticed in the absence of any element or elements, limitation orlimitations, not specifically disclosed herein. Thus, for example, theterms “comprising,” “including,” “containing,” etc. shall be readexpansively and without limitation. Additionally, the terms andexpressions employed herein have been used as terms of description andnot of limitation, and there is no intention in the use of such termsand expressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the claimed technology.Additionally, the phrase “consisting essentially of” will be understoodto include those elements specifically recited and those additionalelements that do not materially affect the basic and novelcharacteristics of the claimed technology. The phrase “consisting of”excludes any element not specified.

In addition, where features or aspects of the disclosure are describedin terms of Markush groups, those skilled in the art will recognize thatthe disclosure is also thereby described in terms of any individualmember or subgroup of members of the Markush group. Each of the narrowerspecies and subgeneric groupings falling within the generic disclosurealso form part of the invention. This includes the generic descriptionof the invention with a proviso or negative limitation removing anysubject matter from the genus, regardless of whether or not the excisedmaterial is specifically recited herein.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges disclosed herein also encompass any and all possible subrangesand combinations of subranges thereof. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths,tenths, etc. As a non-limiting example, each range discussed herein canbe readily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art all languagesuch as “up to,” “at least,” “greater than,” “less than,” and the like,include the number recited and refer to ranges which can be subsequentlybroken down into subranges as discussed above. Finally, as will beunderstood by one skilled in the art, a range includes each individualmember.

All publications, patent applications, issued patents, and otherdocuments (for example, journals, articles and/or textbooks) referred toin this specification are herein incorporated by reference as if eachindividual publication, patent application, issued patent, or otherdocument was specifically and individually indicated to be incorporatedby reference in its entirety. Definitions that are contained in textincorporated by reference are excluded to the extent that theycontradict definitions in this disclosure.

The present technology may include, but is not limited to, the featuresand combinations of features recited in the following letteredparagraphs, it being understood that the following paragraphs should notbe interpreted as limiting the scope of the claims as appended hereto ormandating that all such features must necessarily be included in such

-   A. A compound according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein

-   -   R¹ is H, alkyl, cycloalkyl, awl, or heteroaryl;    -   R² is a substituted or unsubstituted aryl or heteroaryl;    -   R³ is a substituted or unsubstituted cycloalkyl, aryl, or        heteroaryl;    -   and (a) X¹ is N, Y¹ is N, and Z¹ is CH; or (b) X¹ is N, Y¹ is        CH, and Z¹ is N; or (c) X¹ is CH, Y¹ is CH, and Z¹ is CH.

-   B. The compound of Paragraph A, wherein R¹ is C₁-C₆ alkyl, C₄-C₇    cycloalkyl, or phenyl group.

-   C. The compound of Paragraph A or Paragraph B, wherein R¹ is C₁-C₆    alkyl, unsubstituted C₄-C₇ cycloalkyl, or substituted phenyl.

-   D. The compound of any one of Paragraphs A-C, wherein R² is an    unsubstituted heteroaryl or a substituted aryl group where the aryl    group bears 1, 2, or 3 substituents.

-   E. The compound of any one of Paragraphs A-D, wherein R² is an    unsubstituted nitrogen-containing heteroaryl or a substituted phenyl    group where the substituents of the phenyl group are selected from    halogen, nitro, cyano, alkanoyl, carbamoyl, ester, amido, sulfonyl,    sulfonamido, and a trifluoromethyl.

-   F. The compound of any one of Paragraphs A-E, wherein R² is an    unsubstituted six-membered nitrogen-containing heteroaryl or a    substituted phenyl group where the substituents of the phenyl group    are selected from halogen, sulfonyl group, sulfonamido, and    trifluoromethyl.

-   G. The compound of any one of Paragraphs A-F, wherein R³ is    unsubstituted heteroaryl.

-   H. The compound of any one of Paragraphs A-G, wherein the compound    is

or a pharmaceutically acceptable salt of any one thereof.

-   I. The compound of any one of Paragraphs A-H, wherein R² is

-   J. The compound of any one of Paragraphs A-I, wherein X¹ is CH, Y¹    is CH, and Z¹ is CH.-   K. A composition comprising a compound of any one of Paragraphs A-J    and a pharmaceutically acceptable carrier.-   L. A composition comprising a compound of any one of Paragraphs H-J    and a pharmaceutically acceptable carrier.-   M. A composition comprising a pharmaceutically acceptable carrier    and one or more of

or a pharmaceutically acceptable salt of any one thereof.

-   N. A pharmaceutical composition for treating an enterovirus,    paramyxovirus, respiratory virus, flaviviridae virus, bunyaviridae    virus, togaviridae virus, or rabies virus infection, the composition    comprising an effective amount of a compound of any one of    Paragraphs A-J and a pharmaceutically acceptable excipient, wherein    the effective amount of the compound is effective for treating the    enterovirus, paramyxovirus, respiratory virus, flaviviridae virus,    bunyaviridae virus, togaviridae virus, or rabies virus infection.-   O. The pharmaceutical composition of Paragraph N, wherein the    pharmaceutical composition is packaged in unit dosage form.-   P. The pharmaceutical composition of Paragraph N or Paragraph O,    wherein the enterovirus is Coxsackievirus A9, Coxsackievirus A16,    Coxsackievirus B1, Coxsackievirus B2, Coxsackievirus B3-H3,    Coxsackievirus B4, Coxsackievirus B5, Enterovirus 68, Enterovirus    68, Enterovirus 71, Echovirus 6, Echovirus 7, Echovirus 9, Echovirus    11, Echovirus 18, Echovirus 25, Echovirus 30, Poliovirus 1, or    Poliovirus 3.-   Q. The pharmaceutical composition of any one of Paragraphs N-P,    wherein the compound is

or a pharmaceutically acceptable salt of any one thereof.

-   R. A method for inhibiting the replication of an enterovirus,    paramyxovirus, respiratory virus, flaviviridae virus, bunyaviridae    virus, togaviridae virus, or rabies virus in a cell infected with    the enterovirus, paramyxovirus, respiratory virus, flaviviridae    virus, bunyaviridae virus, togaviridae virus, or rabies virus, the    method comprising contacting an effective amount of a compound of    any one of Paragraphs A-J with the cell, wherein the effective    amount of the compound is effective for inhibiting the replication    of the enterovirus, paramyxovirus, respiratory virus, flaviviridae    virus, bunyaviridae virus, togaviridae virus, or rabies virus    infection..-   S. The method of Paragraph R, wherein the enterovirus is    Coxsackievirus A9, Coxsackievirus A16, Coxsackievirus B1,    Coxsackievirus B2, Coxsackievirus B3-H3, Coxsackievirus B4,    Coxsackievirus B5, Enterovirus 68, Enterovirus 71, Echovirus 6,    Echovirus 7, Echovirus 9, Echovirus 11, Echovirus 18, Echovirus 25,    Echovirus 30, Poliovirus 1, or Poliovirus 3.-   T. The method of Paragraph R or Paragraph S, wherein the compound is

or a pharmaceutically acceptable salt of any one thereof.

-   U. A method of inhibiting death of a cell infected with an    enterovirus, paramyxovirus, respiratory virus, flaviviridae virus,    bunyaviridae virus, togaviridae virus, or rabies virus, the method    comprising contacting an effective amount of a compound of any one    of Paragraphs A-J with the cell, wherein the effective amount of the    compound is effective for inhibiting death of the cell.-   V. The method of Paragraph U, wherein the enterovirus is    Coxsackievirus A9, Coxsackievirus A16, Coxsackievirus B1,    Coxsackievirus B2, Coxsackievirus B3-H3, Coxsackievirus B4,    Coxsackievirus B5, Enterovirus 68, Enterovirus 71, Echovirus 6,    Echovirus 7, Echovirus 9, Echovirus 11, Echovirus 18, Echovirus 25,    Echovirus 30, Poliovirus 1, or Poliovirus 3.-   W. The method of Paragraph U or Paragraph V, wherein the compound is

or a pharmaceutically acceptable salt of any one thereof.

-   X. A method of treating a patient or animal infected with an    enterovirus, paramyxovirus, respiratory virus, flaviviridae virus,    bunyaviridae virus, togaviridae virus, or rabies virus, the method    comprising administration of an effective amount of a compound of    any one of Paragraphs A-J to the patient or animal, wherein the    effective amount of the compound is effective for treating the    enterovirus, paramyxovirus, respiratory virus, flaviviridae virus,    bunyaviridae virus, togaviridae virus, or rabies virus infection.-   Y. The method of Paragraph X, wherein the enterovirus is    Coxsackievirus A9, Coxsackievirus A16, Coxsackievirus B1,    Coxsackievirus B2, Coxsackievirus B3-H3, Coxsackievirus B4,    Coxsackievirus B5, Enterovirus 68, Enterovirus 71, Echovirus 6,    Echovirus 7, Echovirus 9, Echovirus 11, Echovirus 18, Echovirus 25,    Echovirus 30, Poliovirus 1, or Poliovirus 3.-   Z. The method of Paragraph X or Paragraph Y, wherein administration    of the effective amount of the compound to the patient or animal    treats the patient or animal infected with the enterovirus,    paramyxovirus, respiratory virus, flaviviridae virus, bunyaviridae    virus, togaviridae virus, or rabies virus.-   AA. The method of any one of Paragraphs X-Z, wherein the    administration comprises oral administration, parenteral    administration, or nasal administration.-   AB. The method of any one of Paragraphs X-AA, wherein the compound    is

or a pharmaceutically acceptable salt of any one thereof.

-   -   Other embodiments are set forth in the following claims, along        with the full scope of equivalents to which such claims are        entitled.

What is claimed is:
 1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H, alkyl, cycloalkyl, aryl, or heteroaryl; R² is aryl orheteroaryl; and R³ is cycloalkyl, aryl, or heteroaryl; wherein IV and R³are each optionally and independently substituted with 1 or moresubstituents independently selected from the group consisting of F, Cl,Br, I, CN, NO₂, ═O, alkyl, haloalkyl, heterocyclylalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, C(NH)H, C(Nalkyl)H, C(NHNH₂)H,C(NHNHalkyl)H, C(NHN(alkyl)₂)H, C(N(alkyl)NH₂)H, C(N(alkyl)NH(alkyl))H,C(N(alkyl)N(alkyl)₂)H, C(NOH)H, C(NOalkyl)H, C(NH)NH_(2,)C(Nalkyl)NH_(2,) C(N(alkyl)₂)NH₂, C(NH)NHalkyl, C(NH)N(alkyl)₂,C(Nalkyl)NHalkyl, C(Nalkyl)N(alkyl)₂, C(O)H, C(O)alkyl, C(O)alkenyl,C(O)NH₂, C(O)NHalkyl, C(O)NHcycloalkyl, C(O)NHheterocyclyl, C(O)NHaryl,C(O)NHheteroaryl, C(O)OH, C(O)Oalkyl, C(O)Ocycloalkyl,C(O)Oheterocyclyl, C(O)Oaryl, C(O)Oheteroaryl, C(O)alkynyl,C(O)cycloalkyl, C(O)heterocyclyl, C(O)aryl, C(O)heteroaryl, NH₂,NH(alkyl), NH(alkenyl), NH(alkynyl), N(alkyl)₂, NHC(O)H, N(alkyl)C(O)H,NHC(O)alkyl, N(alkyl)C(O)alkyl, NHC(O)cycloalkyl,N(alkyl)C(O)cycloalkyl, NHC(O)heterocyclyl, N(alkyl)C(O)heterocyclyl,NHC(O)aryl, N(alkyl)C(O)aryl, NHC(O)heteroaryl, N(alkyl)C(O)heteroaryl,NHC(NH)NH₂, N(alkyl)C(NH)NH₂, NHC(Nalkyl)NH₂, N(alkyl)C(Nalkyl)NH₂,NHC(N(alkyl)₂)NH₂, N(alkyl)C(N(alkyl)₂)NH₂,NHC(NH)NHalkyl,N(alkyl)C(NH)NHalkyl, NHC(NH)N(alkyl)₂, N(alkyl)C(NH)N(alkyl)₂,NHC(Nalkyl)NHalkyl, N(alkyl)C(Nalkyl)NHalkyl, NHC(Nalkyl)N(alkyl)₂,N(alkyl)C(Nalkyl)N(alkyl)₂, NHC(O)NH₂, NHC(O)NHalkyl,NHC(O)NHcycloalkyl, NHC(O)NHheterocyclyl, NHC(O)NHaryl,NHC(O)NHheteroaryl, NHC(O)OH, N(alkyl)C(O)OH, NHC(O)Oalkyl,N(alkyl)C(O)Oalkyl, NHC(O)Ocycloalkyl, N(alkyl)C(O)Ocycloalkyl,NHC(O)Oheterocyclyl, N(alkyl)C(O)Oheterocyclyl, NHC(O)Oaryl,N(alkyl)C(O)Oaryl, NHC(O)Oheteroaryl, N(alkyl)C(O)Oheteroaryl, NHNH₂,NHNH(alkyl), NHN(alkyl)₂, N(alkyl)NH₂,N(alkyl)NH(alkyl),N(alkyl)N(alkyl)₂,NHOH, N(alkyl)OH, NHO(alkyl), N(alkyl)O(alkyl),NHO(aralkyl), N(alkyl)O(aralkyl), NHS(O)₂alkyl, N(alkyl)S(O)₂alkyl,NHS(O)₂heterocyclylalkyl, N(alkyl)S(O)₂heterocyclylalkyl,NHS(O)₂aralkyl, N(alkyl)S(O)₂aralkyl, NHS(O)₂alkenyl,N(alkyl)S(O)₂alkenyl, NHS(O)₂alkynyl, N(alkyl)S(O)₂alkynyl,NHS(O)₂cycloalkyl, N(alkyl)S(O)₂cycloalkyl, NHS(O)₂heterocyclyl,N(alkyl)S(O)₂heterocyclyl, NHS(O)₂aryl, N(alkyl)S(O)₂aryl,NHS(O)₂heteroaryl, N(alkyl)S(O)₂heteroaryl, NH(cycloalkyl),NH(heterocyclyl), NH(aryl), NH(heteroaryl), N(alkyl)cycloalkyl,N(alkyl)heterocyclyl, N(alkyl)aryl, N(alkyl)heteroaryl, NCO, NCS, N₃,N-oxide, OH, OCN, O(alkyl), O(heterocyclylalkyl), O(aralkyl),O(alkenyl), O(alkynyl), O(cycloalkyl), O(heterocyclyl), O(aryl),O(heteroaryl), SH, SF₅, SCN, S(alkyl), S(heterocyclylalkyl), S(aralkyl),S(alkenyl), S(alkynyl), S(cycloalkyl), S(heterocyclyl), S(aryl),S(heteroaryl), S(O)alkyl, S(O)heterocyclylalkyl, S(O)aralkyl,S(O)alkenyl, S(O)alkynyl, S(O)cycloalkyl, S(O)heterocyclyl, S(O)aryl,S(O)heteroaryl, S(O)₂alkyl, S(O)₂heterocyclylalkyl, S(O)₂aralkyl,S(O)₂alkenyl, S(O)₂alkynyl, S(O)₂NH₂, S(O)₂NHalkyl, S(O)₂N(alkyl)₂,S(O)₂NHheterocyclylalkyl, S(O)₂N(alkyl)heterocyclylalkyl,S(O)₂NHaralkyl, S(O)₂N(alkyl)aralkyl, S(O)₂NHalkenyl,S(O)₂N(alkyl)alkenyl, S(O)₂NHalkynyl, S(O)₂N(alkyl)alkynyl,S(O)₂NHcycloalkyl, S(O)₂N(alkyl)cycloalkyl, S(O)₂NHheterocyclyl,S(O)₂N(alkyl)heterocyclyl, S(O)₂NHaryl, S(O)₂N(alkyl)aryl,S(O)₂NHheteroaryl, S(O)₂N(alkyl)heteroaryl, S(O)₂OH, S(O)₂O(alkyl),S(O)₂cycloalkyl, S(O)₂heterocyclyl, S(O)₂aryl, S(O)₂heteroaryl,cycloalkyl, heterocyclyl, aryl, and heteroaryl.
 2. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein:


3. The compound of claim 2, or a pharmaceutically acceptable saltthereof, wherein R² is 4-fluorophenyl, pyridin-2-yl, or pyridin-3-yl. 4.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R¹ is C₁-C₆ alkyl, C₄-C₇ cycloalkyl, or phenyl.
 5. The compoundof claim 1, or a pharmaceutically acceptable salt thereof, wherein R¹ isC₁-C₆ alkyl.
 6. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R₂ is phenyl or heteroaryl, wherein thephenyl is substituted with 1, 2, or 3 independently selectedsubstituents.
 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R₂ is phenyl or a nitrogen-containingheteroaryl, wherein the phenyl is substituted with 1 or moresubstituents independently selected from the group consisting of F, Cl,Br, I, CN, NO₂, CF₃, C(O)alkyl, C(O)NH₂, C(O)NHalkyl, C(O)NHcycloalkyl,C(O)NHheterocyclyl, C(O)NHaryl, C(O)NHheteroaryl, C(O)Oalkyl,C(O)Ocycloalkyl, C(O)Oheterocyclyl, C(O)Oaryl, C(O)Oheteroaryl,NHC(O)Oalkyl, N(alkyl)C(O)Oalkyl, NHC(O)Ocycloalkyl,N(alkyl)C(O)Ocycloalkyl, NHC(O)Oheterocyclyl, N(alkyl)C(O)Oheterocyclyl,NHC(O)Oaryl, N(alkyl)C(O)Oaryl, NHC(O)Oheteroaryl,N(alkyl)C(O)Oheteroaryl, NHS(O)₂alkyl, N(alkyl)S(O)₂alkyl,NHS(O)₂heterocyclylalkyl, N(alkyl)S(O)₂heterocyclylalkyl,NHS(O)₂aralkyl, N(alkyl)S(O)₂aralkyl, NHS(O)₂alkenyl,N(alkyl)S(O)₂alkenyl, NHS(O)₂alkynyl, N(alkyl)S(O)₂alkynyl,NHS(O)2cycloalkyl, N(alkyl)S(O)₂cycloalkyl, NHS(O)₂heterocyclyl,N(alkyl)S(O)₂heterocyclyl, NHS(O)₂aryl, N(alkyl)S(O)₂aryl,NHS(O)₂heteroaryl, N(alkyl)S(O)₂heteroaryl, S(O)₂alkyl,S(O)₂heterocyclylalkyl, S(O)₂aralkyl, S(O)₂alkenyl, S(O)₂alkynyl,S(O)₂cycloalkyl, S(O)₂heterocyclyl, S(O)₂aryl, S(O)₂heteroaryl,S(O)₂NH₂, S(O)₂NHalkyl, S(O)2N(alkyl)₂, S(O)₂NHheterocyclylalkyl,S(O)₂N(alkyl)heterocyclylalkyl, S(O)₂NHaralkyl, S(O)₂N(alkyl)aralkyl,S(O)₂NHalkenyl, S(O)₂N(alkyl)alkenyl, S(O)₂NHalkynyl,S(O)₂N(alkyl)alkynyl, S(O)₂NHcycloalkyl, S(O)₂N(alkyl)cycloalkyl,S(O)₂NHheterocyclyl, S(O)₂N(alkyl)heterocyclyl, S(O)₂NHaryl,S(O)₂N(alkyl)aryl, S(O)₂NHheteroaryl, and S(O)₂N(alkyl)heteroaryl. 8.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is phenyl or a 6-membered, nitrogen-containing heteroaryl,wherein the phenyl is substituted with 1 or more substituentsindependently selected from the group consisting of F, Cl, Br, I, CF₃,NHS(O)₂alkyl, N(alkyl)S(O)₂alkyl, NHS(O)₂heterocyclylalkyl,N(alkyl)S(O)₂heterocyclylalkyl, NHS(O)₂aralkyl, N(alkyl)S(O)₂aralkyl,NHS(O)₂alkenyl, N(alkyl)S(O)₂alkenyl, NHS(O)₂alkynyl,N(alkyl)S(O)₂alkynyl, NHS(O)₂cycloalkyl, N(alkyl)S(O)₂cycloalkyl,NHS(O)₂heterocyclyl, N(alkyl)S(O)₂heterocyclyl, NHS(O)₂aryl,N(alkyl)S(O)₂aryl, NHS(O)₂heteroaryl, N(alkyl)S(O)₂heteroaryl,S(O)₂alkyl, S(O)₂heterocyclylalkyl, S(O)₂aralkyl, S(O)₂alkenyl,S(O)₂alkynyl, S(O)₂cycloalkyl, S(O)₂heterocyclyl, S(O)₂aryl,S(O)₂heteroaryl, S(O)₂NH2, S(O)₂NHalkyl, S(O)₂N(alkyl)₂,S(O)₂NHheterocyclylalkyl, S(O)₂N(alkyl)heterocyclylalkyl,S(O)₂NHaralkyl, S(O)₂N(alkyl)aralkyl, S(O)₂NHalkenyl,S(O)₂N(alkyl)alkenyl, S(O)₂NHalkynyl, S(O)₂N(alkyl)alkynyl,S(O)₂NHcycloalkyl, S(O)₂N(alkyl)cycloalkyl, S(O)₂NHheterocyclyl,S(O)₂N(alkyl)heterocyclyl, S(O)₂NHaryl, S(O)₂N(alkyl)aryl,S(O)₂NHheteroaryl, and S(O)₂N(alkyl)heteroaryl.
 9. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R² is4-fluorophenyl, pyridin-2-yl, or pyridin-3-yl.
 10. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R³ isheteroaryl.
 11. The compound of claim 1, wherein the compound isselected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 12. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and acompound of claim 1, or a pharmaceutically acceptable salt thereof. 13.A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of claim 11, or a pharmaceutically acceptablesalt thereof.
 14. A method for inhibiting the replication of a virus ina cell, the method comprising contacting the cell with an effectiveamount of a compound of claim 11, or a pharmaceutically acceptable saltthereof, or the pharmaceutical composition of claim 13; wherein the cellis infected by a virus selected from the group consisting of abunyaviridae virus, an enterovirus, a flaviviridae virus, aparamyxovirus, rabies virus, a respiratory virus, and a togoviridaevirus.
 15. The method of claim 14, wherein the enterovirus infection iscaused by an enterovirus selected from the group consisting ofcoxsackievirus A9, coxsackievirus A16, coxsackievirus 1, coxsackievirusB2, coxsackievirus B3-H3, coxsackievirus B4, coxsackievirus B5,echovirus 6, echovirus 7, echovirus 9, echovirus 11, echovirus 18,echovirus 25, echovirus 30, enterovirus 68, and enterovirus
 71. 16. Amethod for inhibiting the death of a cell infected by a virus, themethod comprising contacting the cell with an effective amount of acompound of claim 11, or a pharmaceutically acceptable salt thereof, orthe pharmaceutical composition of claim 13; wherein the cell is infectedby a virus selected from the group consisting of a bunyaviridae virus,an enterovirus, a flaviviridae virus, a paramyxovirus, rabies virus, arespiratory virus, and a togoviridae virus.
 17. The method of claim 16,wherein the enterovirus infection is caused by an enterovirus selectedfrom the group consisting of coxsackievirus A9, coxsackievirus A16,coxsackievirus 1, coxsackievirus B2, coxsackievirus B3-H3,coxsackievirus B4, coxsackievirus B5, echovirus 6, echovirus 7,echovirus 9, echovirus 11, echovirus 18, echovirus 25, echovirus 30,enterovirus 68, and enterovirus
 71. 18. A method for treating a virusinfection in an animal or patient, the method comprising administeringto the animal or patient in need thereof an effective amount of acompound of claim 11, or a pharmaceutically acceptable salt thereof, orthe pharmaceutical composition of claim 13; wherein the virus infectionis caused by a virus selected from the group consisting of abunyaviridae virus, an enterovirus, a flaviviridae virus, aparamyxovirus, rabies virus, a respiratory virus, and a togoviridaevirus.
 19. The method of claim 18, wherein the enterovirus infection iscaused by an enterovirus selected from the group consisting ofcoxsackievirus A9, coxsackievirus A16, coxsackievirus 1, coxsackievirusB2, coxsackievirus B3-H3, coxsackievirus B4, coxsackievirus B5,echovirus 6, echovirus 7, echovirus 9, echovirus 11, echovirus 18,echovirus 25, echovirus 30, enterovirus 68, and enterovirus
 71. 20. Amethod for treating an enterovirus infection in an animal or patient,the method comprising administering to the animal or patient in needthereof an effective amount of a compound of claim 11, or apharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition of claim
 13. 21. The method of claim 20, wherein theenterovirus infection is caused by an enterovirus selected from thegroup consisting of coxsackievirus A9, coxsackievirus A16,coxsackievirus 1, coxsackievirus B2, coxsackievirus B3-H3,coxsackievirus B4, coxsackievirus B5, echovirus 6, echovirus 7,echovirus 9, echovirus 11, echovirus 18, echovirus 25, echovirus 30,enterovirus 68, and enterovirus 71.